PROJECT SUMMARY Temporal lobe epilepsy (TLE) is the most common form of refractory human epilepsy, and mesial temporal lobe epilepsy (MTLE) is the most common form of TLE. MTLE is characterized by focal seizures, neuropsychological deficits, neuroinflammation, and hippocampal alterations that include neuronal loss. MTLE is often refractory to available antiepileptic drugs (AEDs), creating a need for the development of treatments that can more effectively mitigate the broad spectrum of clinical features associated with MTLE, while minimizing unwanted side effects. It is increasingly recognized that dysregulated neuroinflammatory responses can contribute to the pathogenesis of several forms of epilepsy, including MTLE, and is thus an important consideration in the development of new drug targets. Cannabinoid 2 receptors (CB2Rs) are receiving increasing attention for their ability to safely confer anti-inflammatory and neuroprotective properties in models of neurological disorders such as traumatic brain injury and stroke. While much less research has been conducted on the role of CB2Rs in epilepsy, pre-treatment with CB2R agonists has been shown to increase resistance to acutely induced seizures in mice. In addition, we provide Preliminary Data demonstrating that CB2R knockout mice are seizure susceptible, and resistance to induced seizures in wildtype mice is increased following the administration of EC21a, a novel CB2R positive allosteric modulator (PAM). Given that reactive gliosis and increased pro-inflammatory cytokine release in MTLE are important contributors to the development of spontaneous seizures, we hypothesize that that activation of CB2Rs will effectively ameliorate these inflammatory changes thereby reducing seizure generation and co- morbid behavioral abnormalities in MTLE. We will test this hypothesis by evaluating and comparing the ability of two CB2R selective compounds, JWH-133 (a CB2R agonist) and EC21a (a PAM), to reduce inflammation and neuron loss (Aim 1) and to mitigate the development of spontaneous seizures and behavioral abnormalities (Aim 2) in the intrahippocampal-kainic acid (IH-KA) mouse model of MTLE. We will also compare the effect of early and delayed treatment initiation. If successful, this proposal will establish the potential of CB2Rs as a novel therapeutic target for the treatment of MTLE and potentially other forms of epilepsy associated with significant neuroinflammation.